The hyaloid vascular system (HVS) is a transiently existing network of capillaries that function to nourish the immature lens and primary vitreous of the developing eye. The hyaloid artery (HA) runs from the back of the eye to the embryonic lens giving rise to a capillary plexus that surrounds the lens, consisting of the vasa hyaloidea propria (VHP), the tunica vasculosa lentis (TVL) and the pupillary membrane (PM). The HVS provides a useful system to investigate physiologically relevant angiogenesis and vascular remodeling processes.
The first elements of the human hyaloid vasculature to undergo regression are the VHP, followed by the TVL, PM and lastly the main hyaloid trunk, commencing at 12 weeks of gestation (WG) and culminating in the involution of the entire hyaloid by 35-36 WG (Mann I. The Development of the Human Eye. Pp 201-32. Grune & Stratton Inc: New York, 1964.). In humans, failure of the hyaloid vascular system to regress can lead to a condition known as persistent hyperplastic primary vitreous (PHPV), which can result in permanent blindness if left untreated.
Mitchell and coworkers showed that in mice the hyaloid vascular system is first recognized at embryonic day 10.5 (E10.5), is complete by E13.5 and regresses postnatally prior to eyelid opening (Mitchell C A, et al., Dev. Dyn. 213(3):322-33 (1998)). During mouse development, the longer branches of the TVL and the longer hyaloid vessels are removed by post-gestational day 16 (P16) (Mitchell C A, et al., Dev. Dyn. 213(3):322-33 (1998)). Ito et al. presented partially similar results, showing that the PM had completely disappeared by P16, and the VHP had disappeared between P12 and P16, but the TVL and the hyaloid artery remained even at P16 (Ito and Yoshioka, Anat. Embryol. (Berl). 200(4):403-11 (1999)). Smith showed a gradual disappearance of the TVL and hyaloid artery from P14 to P30 (Smith, Systematic evaluation of the Mouse Eye: Anatomy, Pathology, and Biomethods. Pp 45-63. Sunders, 2002.).
Previous hypotheses of the mechanism of regression of the hyaloid vascular system included the following:
A. The reduction or the cessation of the blood flow into the HVS was thought to be one of the major triggering factors of the regression in these vessels. A change in the blood flow distribution (Bischoffet al., Graefes Arch. Clin. Exp. Ophthalmol. 220 (6):257-63 (1983)) and competition between the blood vessels in the retina and the lens for the blood flow can lead to the degeneration of the HVS when the retinal blood vessels become larger and require more nutrients.
B. Vascular obstruction, physical vascular stretching, localized circulatory stasis, and arterial vasoconstriction were regarded as triggering factors of the regression of the HVS (Jack, Am. J. Ophthalmol. 74 (2):261-72 (1972); Latker and Kuwabara, Invest. Ophthalmol. Vis. Sci. 21 (5):689-99 (1981)). The regression occurs first in those vessels that were hemodynamically disadvantaged and consequently had less blood flow.
C. Meeson et al. have shown that the occurrence of apoptosis in the PM strictly correlated to the flow status; as the flow decreased the appearance of apoptosis in capillaries increased (Meeson et al., Development. 122(12):3929-38 (1996)). The same correlation may exist in the hyaloid vascular system. As the main role of the HVS is supposed to be to nourish the retina before the maturation of retinal vessels, the HVS may regress after the completion of these vessels.
D. Macrophages may also be required in the programmed regression of the PM and the HVS (Lang and Bishop, Cell. 13; 74 (3):453-62 (1993); Lang et al., Development. 120 (12):3395-403 (1994); Diez-Roux and Lang, Development. 124 (18):3633-8 (1997)).
E. The anti-angiogenic ability of the vitreous humor and vitreous extracts may also be important in the regression of the TVL (Preis et al., Am. J. Ophthalmol. 84 (3):323-8 (1977); Felton et al., Arch. Ophthalmol. 97 (9):1710-3 (1979); Lutty et al., Invest. Ophthalmol. Vis. Sci. 24 (1):52-6 (1983); Taylor and Weiss, Biochem Biophys Res Commun. 133 (3):911-6 (1985); Zhu et al., Aust. N. Z. J. Ophthalmol. 25 Suppl 1:S57-60 (1997); Ramesh et al., Br. J. Ophthalmol. 88 (5):697-702 (2004)). Hyalocytes play also a role in the regression of the TVL (McMenamin et al., Invest. Ophthalmol. Vis Sci. 43 (7):2076-82 (2002)). Lutty et al. have demonstrated that the hyalocytes produce and process transforming growth factor-β (TGF-β) which may inhibit is the proliferation of the vascular endothelial cells in this system (Lutty et al., Invest. Ophthalmol. Vis. Sci. 34 (3):477-87 (1993)).
F. Several survival factors may protect cells from apoptosis, including fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). A reduction in levels of these growth factors below a critical threshold may lead to the induction of an apoptotic program.
The role of VEGF in the maintenance of the VHP is not clear. Feenay et al. demonstrated that the TVL degeneration was unexpectedly uninfluenced by treatment with a VEGF A antibody, suggesting that programmed regression is independent of VEGF A, or that the development and maturation of the lens had gone beyond the point of the plasticity and susceptibility to certain growth factors (Feeney et al., Invest. Ophthalmol. Vis. Sci. 44 (2):839-47 (2003)).